Dyslipidemia and diseases related to dyslipidemia e.g. atherosclerosis, coronary artery disease, stroke, etc., are major causes of death, morbidity, and economic loss. Plasma lipids, especially cholesterol fractions, are recognized as having a significant role in cardiovascular health. Favorable modulation of plasma lipid such as triglycerides, HDL cholesterol, and LDL cholesterol is desirable.
International application WO 03/015771 A1 discloses certain isoxazoles for use in treating diseases mediated by the FXR NR1H4 receptor. International application WO 00/37077 discloses certain isoxazoles that bind to the farnesoid X receptor (FXR). International application WO 2004/048349 A1 discloses compounds useful as farnesoid X receptor agonists. International application WO 98/28269 discloses compounds useful as factor Xa inhibitors.
The nuclear hormone receptors, FXRs, regulate the metabolism of plasma cholesterol and HDL. Thus, compounds which modulate the FXRs would enhance the profile of lipid regulation, particularly increased HDL levels. Such compounds are desirable and would be useful for treatment of disorders characterized by or resulting from an undesirable lipid profile including dyslipidemia, atherosclerosis, diabetes and related diseases. The present invention provides novel, selective and potent FXR agonists for beneficial regulation of lipid profiles including raising HDL levels.